Aminoalkanoyl phenothiazine deriv



Patented Apr. 8, 1952 v.

NITED STATES PATENT orncs AMINOALKANOYL PHENOTHIAZINE DERIV- ATIVES ANDTHE PRODUCTION THEREOF John W. Cusic, Skokie, 111., assignor to G. D.

seasrle & Co., Skokie, 111., a corporation of Illino N o Drawing.Application April 21, 1948,

Serial No. 22,505

1 This invention relates to compounds of the phenothiazine series havingin the 10-position an aminoalkanoyl radical, to salts thereof, and toprocesses for producing such compounds. More particularly, thisinvention relates to new compositions of matter having the followinggeneral structural formula wherein X represents S, S or S02,Alli-represents a lower alkylene radical, and B represents a secondaryor tertiary aliphatic-type amino radical, as well as to acid additionand quaternary ammonium salts of such bases.

The heterocyclic compounds and radicals in this aplication are named andnumbered according to the rules approved by the American Chem-' terwhich are of value for the foregoing uses. It

is a further object to provide simple and efficient methods formanufacturing such substances.

In the foregoing general structural formulaf Alk represents loweralkylene radicals containing between 1 and carbon atoms, and preferablyhaving 1 to 3 carbon atoms between the CO The radical All: is a bivalentradand B groups. ical derived from a saturated aliphatic hydrocarbonradical, and includes such radicals as; methylene, ethylene, propylene,the butylenes and amylenes, and trimethylene, tetrame'th'ylene, andpolymethylene radicals containing 1 'to"10 carbon atoms. an aprimary (i.e., secondary or'tertiary) amino radical derived from an aliphatic oraliphatictype amine having an ionization constant in the range of about'10- to 10- such as the lower monoand dialkylamines and heterocyclicamines which are aliphatic in nature, including morpholine, piperidine,pyrrolidine, thiamorpholine, lupetidine, piperazine, and related cyclicThe amino radical B represents 13 Claims. (c1. 2so 243) amines. Thealkylene radical, AIR, and the amino group, B, can be combined in acyclic. amino structure such as the 4-piperidyl, 2-.

imidazolinomethyl or Z-piperidylmethyl radicals.

vB can be derived from alkanolamines such as ethanolamine,isopropanolamine, methylethanolamine and the like, aswell as esters ofsuchamines; as for instance acetoxyethylamine. The phenothiazine nucleusof the foregoing compounds may be substituted in the 'benzenoid rings byhalogen, alkyl or alkoxyl radicals. r

N-oxides of the compounds of this inventio can be obtained by oxidizinga tertiary amine of the above general formula with 30-90% hydro-;

gen peroxide in an inert solvent such as alcohol.-

Such oxides are generally water-soluble crystalline substances and havethe type formula wherein R. and a represent two aliphatic radi-L cals ortogether represent the elements which with N form an aliphatic-typecyclic amino radical. The oxidation usually takes place on both. thenitrogen and sulfur atoms, producing an N-oxide as well as anS-oxidegroup.

The amino compounds which makeup this invention are only slightlysoluble in water, but are generally soluble in the common organicsolvents. They readily form salts with acids, which salts are generallywater soluble. Among the acids which are suitable for forming suchsaltsare hydrochloric, hydrobromic, sulfuric, phosphoric, tartaric,citric, sulfamic, acetic malic, maleic, benzoic, and similar commonorganic and inor-.

gani'c acids which provide anions which arenontoxic in usual dosages.The '8-halogenated xanthines such as B-chlorotheophylline, 8-bromo-;-

theophylline, and 8-chlorotheobromine are also satisfactory. Salts mayalso be formed by reacting the basic ketones with reactive esters ofstrong acids, to form-quaternary ammonium salts. Such salts can beformed, forexample, by reaction with esters such as methyl iodide,methyl chloride, ethyl bromide, propyl chloride, ethylene bromohydrin,propylene chlorohydrin, benzylchloride, phenethyl bromide, dimethylsulfate, methyl toluenesulfonate, ethyl ben'zene sulfonate,,B-acetoxyethyl bromide, and related esters. I The compounds of thisinvention may be pre pared by treating a compound having the followingformula PCOA1k-X, wherein P represents a radical of the phenothiazineseries, .Alk is a lower alkylene radical, and X represents halogen, witha primary or second (i. e.. atertiary) aliphatic or aliphatic -typ'eamine of the formula I-IB, preferably at elevated temperature, in thepresence of an inert solvent; In practice, it is preferred to use 2 to 3moles of the amine for each mole of ,haloalkanoylphenothiazine, in orderthat excess amine may bind the halogen acid split out during thereaction. It is preferrad to run the reaction at temperatures of therange of 50-150 centigrade for a period of several hours. At thecompletion of the reaction, the amine salt is removed and the solutionof the aminoalkanoyl phenothiazinebase in the organic solvent isisolated. The base may be obtained in a state of ,purity by conventionalprocedures such as evaporation of the solvent and distillation, or thebase may be converted to the acid addition salt by treatment of thesolution with an equivalent amount of acid.

My invention is disclosed in further detail by the following examples,which present specific embodiments of my invention, without, however,limiting it in spirit or in scope. The amounts of materials are given inparts by weight.

Example 1 112 parts of phenothiazine and "73 parts of 18-chloropropionyl chloride in 550 parts of benzene are vrefluxed for 20hours. The hot solution is filtered and evaporated. The residue .of -13chloropropionylphenothiazine is recrystallized from alcohol, and meltsat *135- 136 C.

150 parts of 10- 3-chloropropionylphenothiazine and 85 parts ofpiperidine in 870 parts of dry toluene are refluxed for 6 hours. Thecooled solution is extracted with dilute mineral acid, and the acidextract is made alkaline and extracted with ether. The ether extract isdried and evaporated. The residue oflo-e-piperidinopropionylphenothiazine distils at 220-230 C. at 3millimeters pressure. It is converted to the hydrochloride by treating adry ether solution of the base with absolute alcoholic hydrogenchloride. The hydrochloride so formed is recrystallized from isopropanoland melts at '230-205'C. The base has the formula CHaOH:

OCHzCHzN CH1 CHaCH:

N-C O-GHyCHr-N Example 2 29 parts of L0-eechloropropionylphenothiazineand 12 parts of dimethylamine in 80 parts of methyl ethyl ketonecontaining 0.5 part of potas-' sium iodide are heated, in a closedvessel at 150-65 C. for 48 hours. The cooled reaction mix- CHa Hn tureis extracted with dilute mineral acid. The mineral acid solution is madealkaline and extracted with ether. After removal of the ether, theresidue of 10-fl-dimethylaminopropionylphenothiazine is crystallizedfrom petroleum ether andme'lts at 86-88 C. When dissolved in ether andtreated with absolute alcoholic hydrogen chloride, it forms acrystalline hydrochloride. The base has the structural formula In .asimilar manner using 35 parts of dibutylamine in place of thedimethylamine one obtains 10-,8-dibutylaminopropionylphenothiazine,which has the following structural formula KI I) Example 3' Example 4 50parts of phenothiazine and 36 parts of 13-. chlorobutyryl chloride in350partsof dry toluene are refluxed for about 15 hours. The hot solutionis treated with decolorizing charcoal, :filtered and evaporated. Theresidue of lo-fi-chlorobutyrylphenothiazine is recrystallized fromalcoholandmelts at 158'-160 C.

5.1 parts of l0-,B-chlorobutyrylphenothiazine and ,18 parts ofdimethylamine in partsoi. acetone containing 1 part of potassium iodideare heated in a closed vessel at 60 C. for 5 days. At the end-of thattime the solution is evaporated and the residue of 10e-dimethylaminobutyrylphenothiazine crystallizes on standing. Afterrecrystallization from petroleum ether, the base melts-at 90,9.l C. .Thehydrochloride is prepared by treating a dryether-benzene solution ofthe. base with absolute alcoholic hydrogen chloride. The .10dimethylaminobutyrylphenothiazine hydrochloridegis recrystallized frommethyl ethyl ketone in the presence of decolor-izing charcoal, and meltsfat-136F138? C. The base has the formula.

I By the reaction of the same quantities of l0-chlorobutyrylphenothiazine (produced from 8 phenothiazine and-chlorobutyryl. chloride by the above process) and dimethylaniin'e inacetone containing a trace of potassium iodide there is formed l--dimethylaminobutyrylphenothiazine. This substance has the formula s I-Co-cmomcnr-Mom a Emample 29 parts of -18-climethylaniinobutyrylpheno-vthiazine and 8 parts of methyl chloride in fit) parts of methyl ethylketone are heated a closed vessel for hour at 60 C. and allowedto standfor hours at room temperature. 'Ihe heavy precipitate of the quaternarysalt, 10 -;3-dimethylaminobutyrylphenothiazine methochloride, is removedby filtration, dried and recrystallized from isopropanol. This saltmelts at By the same procedure, using parts of be zyl chloride, there isformed thejcorresponding quaternary salt, 10-p-dimethylaminobutyylphenothiazine benzylchloride. 1'

Example 6 Other compounds whichjare produced by the foregoing proceduresinclude the following:

A. 10-13-isopropylaminovalerylphenothiazine B. 10--pyrrolidinobutyrylphenothiazine CHICK:

I OH: E:

0. 10-methylethylaminoacetylphenothiazine D. 10 8dimethylaminopropionylphenothiazine 5-monoxide N-oxide E. 10-;9-dibutylaminopropionylphenothiazine 5- monoxide Example 7 A mixture of 58parts of lo-p-chloropropionylphenothiazine and 40 parts of diethylaminein parts of methylethyl ketone containing 1 part of potassium iodide isheated in a closed reactor for 5 days'at 60-65" C. At the end of thisperiod the solvent is removed and a portion of the residue of10-fi-diethylaminopropionylphenothiazine is distilled at 210-212 C. at 2mm. pressure. It :forms' a crystalline hydrochloride melting at about163-164 C. v

The base has the formula By the same method 10 parts of IO-B-chloropropionylphenothiazine are reacted with 7 parts of methylethanolamineand there is produced 10 fl methylethanolaminopropionylphenothiazine,which has the formula wherein All; is a lower alkylene radical and R andR are lower alkyl radicals.

3. A salt of an aminoalkanoylphenothiazine of the formula wherein n isan integer greater than zero and not more than five and R and R arelower alkyl radicals.

4. A salt of an aminopropionylphenothiazine of the formula wherein R andR are lower alkyl radicals.

7 V 5. A salt 01 .;10efi-dialkylaminopropionylphenothiazine. r

6. .A salt of 10-fi-dimethylaminopropionylphenothiazine. "7. 10 ,8vdimethylaminopropionylphenothia-- zinehydrochloride. V v 8. A salt ofan aminopropionylphenothiazine having the formula V i N CO--CHqCH;-M3011)).

wherein n, is an integer greater than vthree and notmo're than five. V

9'. A salt of 10-;3-piperidinopropionylphenothiazine. r

10. 10 B piperidinopropionylphenothiazine hydrochloride.

11. The process of producing a" salt of an aminoalkanoylphenothiazine ofthe formula s N-c O-Alk-ii v wherein Alk is a lower alkylene radical andB is an amino radical selected from the group consisting of monofloweralkyl) amino, di(lower alkyDamino, l-piperidino, l-pyrrolidino and v4- amorpholino. nadica1s','which comprises heating a compoundof-theiormula 7V s I No O-Alk-X wherein is a halogen, with an amine of the formulaisolating the basic aminoalkanoylphenothiazine thus.formedlandiconverting said basic aminoalkanoylphenothiaz'ineto asalt.

"12. The process of ,producing a salt of v a10efi-dialkylaminopropionylphenothiazine which comprises heating, a.10-fl-ha1opropiony1phenothiaz'ine with a,di(1ower alkyl) amine in aninert solvent, recovering therefrom the basic vphenothiazine' compound,and converting said 10-13- di'alkyl-aminopropionylphenothiazine 'to asalt.

No references cited:

1. A MEMBER OF THE GROUP CONSISTING OF AMINOALKANOYLPHENOTHIAZINEDERIVATIVE AND SALTS THEREOF, SAID AMINOAKYANOYLPHENOTHIAZINE DERIVATIVEHAVING THE FORMUAL